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Determinants of Penetrance and Variable Expressivity in Monogenic Metabolic Conditions Across 77,184 Exomes

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Determinants of Penetrance and Variable Expressivity in Monogenic Metabolic Conditions Across 77,184 Exomes medRxiv preprint doi: https://doi.org/10.1101/2020.09.22.20195529; this version posted September 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes Julia Goodrich1, Moriel Singer-Berk1, Rachel Son1, Abigail Sveden1, Jordan Wood1, Eleina England1, Joanne B. Cole1, Ben Weisburd1, Nick Watts1, Zachary Zappala1, Haichen Zhang2, Kristin A. Maloney2, Andy Dahl3, Carlos A. Aguilar-Salinas4, Gil Atzmon5-7, Francisco Barajas-Olmos8, Nir Barzilai5,7, John Blangero9, Eric Boerwinkle10,11, Lori L. Bonnycastle12, Erwin Bottinger13, Donald W Bowden14-16, Federico Centeno- Cruz8, John C. Chambers17,18, Nathalie Chami13,19, Edmund Chan20, Juliana Chan21- 24, Ching-Yu Cheng25,26,27, Yoon Shin Cho28,Cecilia Contreras-Cubas8, Emilio Córdova8, Adolfo Correa29, Ralph A. DeFronzo30, Ravindranath Duggirala9, Josée Dupuis31, Ma. Eugenia Garay-Sevilla32, Humberto García-Ortiz8, Christian Gieger33, Benjamin Glaser34, Clicerio González-Villalpando35, Ma Elena Gonzalez36, Niels Grarup37, Leif Groop38,39, Myron Gross40, Christopher Haiman41, Sohee Han42, Craig L Hanis10, Torben Hansen37, Nancy L. Heard-Costa43,44, Brian E Henderson41, Juan Manuel Malacara Hernandez32, Mi Yeong Hwang42, Sergio Islas-Andrade8, Marit E Jørgensen45-47, Hyun Min Kang48, Bong-Jo Kim42, Young Jin Kim42, Heikki A. Koistinen49-51, Jaspal Singh Kooner52-55, Johanna Kuusisto56, Soo-Heon Kwak57, Markku Laakso56, Leslie Lange58, Jong-Young Lee59, Juyoung Lee42, Donna M. Lehman30, Allan Linneberg60-62, Jianjun Liu63, 20, 64, Ruth J.F. Loos13,19, Valeriya Lyssenko38,65, Ronald C. W. Ma21-24, Angélica Martínez-Hernández8, James B. Meigs1,66,67, Thomas Meitinger68,69, Elvia Mendoza- Caamal8, Karen L. Mohlke70, Andrew D. Morris71,72, Alanna C. Morrison10, Maggie CY Ng14-16, Peter M. Nilsson73, Christopher J. O’Donnell74-77, Lorena Orozco8, Colin N. A. Palmer78, Kyong Soo Park57,79,80, Wendy S. Post81, Oluf Pedersen37, Michael Preuss13, Bruce M. Psaty82,83, Alexander P. Reiner84, Cristina Revilla-Monsalve85, Stephen S Rich86, Jerome I Rotter87, Danish Saleheen88-90, Claudia Schurmann13,91,92, Xueling Sim63, Rob Sladek93-95, Kerrin S Small96, Wing Yee So21-23, Xavier Soberón8, Timothy D Spector96, Konstantin Strauch97,98, Tim M Strom99,68, E Shyong Tai63,20,27, Claudia H.T. Tam21-23, Yik Ying Teo63,100,101, Farook Thameem102, Brian Tomlinson103, Russell P. Tracy104,105, Tiinamaija Tuomi39,106-108, Jaakko Tuomilehto109-112, Teresa Tusié-Luna113,114, Rob M. van Dam63,20,115, Ramachandran S. Vasan43,116, James G Wilson117, Daniel R Witte118,119, Tien-Yin Wong25, 26, 27, Lizz Caulkins1, Noël P. Burtt1, Noah Zaitlen3, Mark I. McCarthy120-122, Michael Boehnke48, Toni I. Pollin2, Jason Flannick1,123,124, Josep M. Mercader1,125,126, Anne O’Donnell-Luria1,123,124, Samantha Baxter1, Jose C. Florez1,125,126, Daniel MacArthur1,127,128, Miriam S. Udler-Aubrey1,125,126, for AMP-T2D-GENES Consortia Affiliations 1 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 2 School of Medicine, University of Maryland Baltimore, Baltimore, MD, USA. 3 Department of Neurology, UCLA, Los Angeles, California. 4 Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico. 5 Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA. 6 Faculty of Natural Science, University of Haifa, Haifa, Israel. 7 Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA. 8 Instituto Nacional de Medicina Genómica, Mexico City, Mexico. 9 Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Brownsville and Edinburg, TX, USA 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.09.22.20195529; this version posted September 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 10 Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA 11 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA 12 Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 13 The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 14 Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. 15 Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. 16 Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA 17 Department of Epidemiology and Biostatistics, Imperial College London, UK 18 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore 19 The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, NY, USA. 20 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore 21 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. 22 Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, The Chinese University of Hong Kong, Hong Kong, China. 23 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China. 24 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. 25 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 26 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore. 27 Duke-NUS Medical School, Singapore, Singapore. 28 Department of Biomedical Science, Hallym University, Chuncheon, South Korea. 29 Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. 30 Department of Medicine, University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio), San Antonio, TX, USA 31 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 32 Department of Medical Science, División of Health Science. University of Guanjuato. Campus León. León, Gto. México. 33 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 34 Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 35 Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Publica, Cuernavaca, Mexico. 36 Centro de Estudios en Diabetes, Mexico City, Mexico. 37 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 38 Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden. 39 Institute for Molecular Genetics Finland, University of Helsinki, Helsinki, Finland. 40 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 41 Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. 42 Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea. 2 medRxiv preprint doi: https://doi.org/10.1101/2020.09.22.20195529; this version posted September 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 43 Boston University and National Heart Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA. 44 Department of Neurology, Boston University School of Medicine, Boston, MA, USA. 45 Steno Diabetes Center Copenhagen, Gentofte, Denmark. 46 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark. 47 Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland. 48 Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA. 49 Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland. 50 University of Helsinki and Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. 51 Minerva Foundation Institute for Medical Research, Helsinki, Finland. 52 Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, London, UK. 53 MRC-PHE Centre for Environment and Health, Imperial College London, London, UK. 54 Imperial College Healthcare NHS Trust, Imperial College London, London, UK. 55 National Heart and Lung Institute, Imperial College London, London, UK. 56 Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland
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